The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer et al., J. Hepatol. 2000, 32, 98-112). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie et al., Scientific American 1999, October, 80-85). An estimated 170 million persons are infected with HCV worldwide. Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplant.
HCV is known to cause at least 80% of posttransfusion hepatitis and a substantial proportion of sporadic acute hepatitis. Preliminary evidence also implicates HCV in many cases of “idiopathic” chronic hepatitis, “cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as Hepatitis B Virus (HBV). A small proportion of healthy persons appear to be chronic HCV carriers, varying with geography and other epidemiological factors. The numbers may substantially exceed those for HBV, though information is still preliminary; how many of these persons have subclinical chronic liver disease is unclear.
HCV has been classified as a member of the virus family Flaviviridae that includes the genera flaviviruses, pestiviruses, and hapaceiviruses, which includes hepatitis C viruses (Rice, C. M., Flaviviridae: The viruses and their replication. In: Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30, 931-959, 1996). HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4 kb. Currently, there are two primary antiviral compounds, Ribavirin and interferon-alpha, which are used for the treatment of chronic HCV infections in humans. The non-structural protein NS5B has been described as an RNA-dependent RNA polymerase that is required for viral replication. This polymerase is an essential component in the HCV replication complex and therefore is an excellent target for drug discovery.
Several 2′-modified nucleoside analogs with potent inhibitory activity against the HCV NS5B polymerase have been identified, including β-D-2′-C-methyl-ribofuranosyl cytidine (1) (e.g., see Sommadossi et al., U.S. Pat. No. 6,914,054 and references therein; and Clark et al., J. Med. Chem. 2005, 48, 5504-5508). Efforts to improve the oral bioavailability of (1) have resulted in the investigation of prodrug derivatives, including synthesis of compounds with acyl and/or α-aminoacyl moieties appended at one or more of the 5′-O, 3′-O, or N-4 positions of the ribonucleoside nucleus (e.g., see Pierra et al., Nucleosides, Nucleotides 2005, 24, 767-770; Pierra et al., J. Med. Chem. 2006, 49, 6614-6620; U.S. Application Publication No. 2004/0077587; International Publication No. WO 2004/002999; and International Application No. WO04/003000). One compound of particular interest is NM 283 (2), the 3′-O-L-valinyl ester of β-D-2′-C-methyl-ribofuranosyl cytidine, which shows good bioavailability in preclinical species and in humans (e.g., see Pierra et al., J. Med. Chem. 2006, 49, 6614-6620). NM 283 is currently undergoing clinical evaluation as a treatment for HCV, where significant antiviral activity has been demonstrated.

One significant problem with oral administration of NM 283 or β-D-2′-C-methyl-ribofuranosyl cytidine is the gastrointestinal (GI) toxicity of the parent nucleoside analog which results in unpleasant side-effects in some patients such as nausea, vomiting and diarrhea. This toxicity may arise as a result of accumulation of the phosphorylated nucleoside analog within intestinal cells, and its incomplete selectivity for inhibition of the viral RNA polymerase relative to mammalian polymerase enzymes. Thus, there is a need for improved prodrugs of (1) having a superior safety and tolerability profile than NM 283 (2). Preferred prodrugs are sufficiently stable in the intestinal lumen and during transit across the enterocyte barrier so that little or no compound (1) is liberated within the intestinal cells themselves. This limits direct exposure of sensitive GI cells to toxic levels of (1). However, once the prodrug has entered the portal circulation and is delivered to the liver, cleavage to compound (1) via enzymatic, chemical, or a combination of enzymatic and chemical means should occur in order that a therapeutically effective concentration of (1) is provided to virally infected cells (hepatocytes).